MAGI3 deficiency unleashes β-catenin conformational change to drive metastatic progression and mTOR inhibitor resistance in ccRCC

Metastatic clear cell renal cell carcinoma (ccRCC) remains lethal due to therapy resistance, and while dysregulated Wnt/β-catenin signaling drives progression, its post-translational regulation is poorly understood. Through multi-omics analysis of TCGA/GEO datasets, we identified MAGI3 as a key metastasis suppressor in ccRCC. Functional validation revealed that MAGI3 loss enhances invasion, migration and metastatic potential in vitro and in vivo. Mechanistically, MAGI3 binds β-catenin's C-terminus via PDZ domains, disrupting intramolecular N-terminus-ARM domain interactions to expose phosphorylation sites, thereby enabling GSK-3β-mediated β-catenin phosphorylation and ubiquitin-dependent degradation. Critically, low MAGI3 hyperactivates β-catenin and drives mTOR inhibitor resistance. Combining Everolimus with the Wnt inhibitor XAV-939 slashed viability and invasion in resistant cells. Clinically, patients whose tumors exhibited high MAGI3 and low β-catenin expression demonstrated significantly improved response to Everolimus therapy. In conclusion, MAGI3 is a critical gatekeeper of β-catenin destruction in ccRCC. Its loss defines a metastatic, therapy-resistant subtype targetable by dual mTOR/Wnt blockade. Therefore, MAGI3 expression may stratify patients for personalized therapy.